Genetic disorders, such as those caused by the absence of, or a defect in, a desirable gene (loss of function) or expression of an undesirable or defective gene or (gain of function), can lead to a variety of disease states.
As an example, GM2 gangliosidosis is a family of three genetic neurodegenerative disorders caused by the accumulation of GM2 gangliosides (GM2). Two of these are due to the deficiency of one of 2 similar but non-identical subunits that comprise heterodimeric β-hexosaminidase A (HexA) which hydrolyzes GM2. Mutations in the α-subunit (encoded by HEXA) of the enzyme HexA lead to Tay-Sachs disease (TSD), wherein mutations in the β-subunit (encoded by HEXB) lead to Sandhoff disease (SD). In these diseases, the malfunctioning protein is unable to play its role in cleaving GM2 ganglioside, whose accumulation within the neurons of the central nervous system is ultimately toxic. The resulting neuronal death induces the primary symptoms of the disease including motor impairment, seizures, and sensory impairments.
Depending on the specific condition, approaches to treating genetic disorder diseases can include dietary changes or replacement of the particular enzyme that is missing. For some conditions, limiting certain substances in the diet can help prevent the buildup of potentially toxic substances that are normally broken down by the missing or defective enzyme. In some cases, enzyme replacement therapy can help compensate for the enzyme shortage. However, diet modification only works for some diseases. Intravenous enzyme replacement therapy generally requires repeated infusions and does not adequately distribute to all tissues requiring enzyme enhancement such as, for some lysosomal diseases, the central nervous system (“CNS”).
A newer approach to treating such diseases is gene transfer based therapy wherein a transgene that can ameliorate the symptoms of the disease is inserted into the genetic material of the patient. For diseases that are caused by the expression of a deleterious protein, such as Huntington's disease or myotonic dystrophy, gene transfer based therapy could potentially also be used wherein a transgene codes for a polynucleotide that could decrease the expression of the deleterious protein or RNA and ameliorate the symptoms of the disease.